The use of human induced Pluripotent Stem Cells (iPSCs) for regenerative medicine is an attractive alternative for the treatment of genetic and degenerative diseases in which an extensive or continuous need of tissue regeneration is required. iPSCs are more easily amenable to in situ gene correction and can be expanded indefinitely retaining a pluripotent and undifferentiated state, and can therefore be used as a constant source of material for cell therapy. Development of iPSC-based therapies for Recessive Dystrophic Epidermolysis Bullosa (RDEB) patients represents an ideal paradigm in this scenario owing to the severe nature of the disease, the demonstration that corrected keratinocytes can have long-term tissue repopulation, and the need for large numbers of stem cells to cover the affected surface area. We have recently demonstrated that Therapeutic Reprogramming (TR) (achieved by genetic correction of RDEB patients-derived iPSC) provides a virtually unlimited source of genetically corrected autologous keratinocytes that can from multi-layered skin with restored functionality and physiological expression of Collagen VII type 1 (Sebastiano et al., 2014). While effective, one of the major bottlenecks of this approach is the many sub-cloning steps required to derive the corrected iPSC clones, with an inherent accumulation of a large number of somatic mutations and karyotype abnormalities (in agreement with a conspicuous body of evidence in the field) that could have unpredictable effects in vivo after transplantation and with serious implications about the safety of iPSC-based therapy in general. This represents a fundamental problem and a preeminent priority that needs to be addressed before translation of iPSC-based technologies to the clinic is put in place. In this proposal we are aiming at tackling this problem by proposing a novel approach to derive genetically corrected iPSCs carrying a slim number of somatic mutations. We believe our proposal will have a fundamental impact on the safety of iPSC-based therapies and will serve as a paradigm for the development of release criteria that will be used to qualify iPSC-banks for any genetic and degenerative disease.